A multi-omics Mendelian randomization study identifies new therapeutic targets for alcohol use disorder and problem drinking.

Integrating proteomic and transcriptomic data with genetic architectures of problematic alcohol use and alcohol consumption behaviours can advance our understanding and help identify therapeutic targets. We conducted systematic screens using genome-wise association study data from ~3,500 cortical proteins (N = 722) and ~6,100 genes in 8 canonical brain cell types (N = 192) with 4 alcohol-related outcomes (N ≤ 537,349), identifying 217 cortical proteins and 255 cell-type genes associated with these behaviours, with 36 proteins and 37 cell-type genes being new. Although there was limited overlap between proteome and transcriptome targets, downstream neuroimaging revealed shared neurophysiological pathways. Colocalization with independent genome-wise association study data further prioritized 16 proteins, including CAB39L and NRBP1, and 12 cell-type genes, implicating mechanisms such as mTOR signalling. In addition, genes such as SAMHD1, VIPAS39, NUP160 and INO80E were identified as having favourable neuropsychiatric profiles. These findings provide insights into the genetic landscapes governing problematic alcohol use and alcohol consumption behaviours, highlighting promising therapeutic targets for future research.